Research in the Bielenberg laboratory focuses on studying the biology of cancer metastasis, the spread of malignant tumor cells from one site in the body to another, through blood vessels and lymphatic vessels. Pancreatic adeno-carcinoma is a devastating disease with only a 4% 5-year survival rate due to the lack of effective therapies. We propose a novel therapeutic approach to pancreatic carcinoma treatment that involves using neuronal guidance molecules called Semaphorins to inhibit neoplastic growth and progression. We have identified a common cell surface receptor that is expressed on pancreatic cancer cells, pancreatic carcinoma-associated endothelial cells (blood vessels), and lymphatic endothelial cells (lymphatic vessels) called Neuropilin 2 (NRP2). It is unusual to find a common target on several cell types within the tumor microenvironment. Therefore, NRP2 is an excellent target for therapy in pancreatic adenocarcinoma. We hypothesize that NRP2 is acting as a VEGF-reservoir in the cancer cells and as an enhancing co-receptor with VEGFR in the endothelial cells. We will test this hypothesis by examining the role of NRP2 in cancer cells as a reservoir for VEGF or as an autocrine mediator of VEGF signaling by overexpressing NRP2 in pancreatic carcinoma cells. In addition, we will test the necessity of NRP2 in tumor-associated angiogenesis and lymphangiogenesis in murine orthotopic pancreatic carcinoma models and in transgenic (K-ras+) pancreatic carcinoma models using NRP2-deficient mice. We predict that mice lacking NRP2 in the endothelial cells will have decreased tumor size, decreased proliferating capillaries (angiogenesis), decreased lymphatic vessel area, and decreased metastatic potential. Lastly, we hypothesize that Semaphorin 3F (SEMA3F), an inhibitory ligand of NRP2, will inhibit (lymph)-angiogenesis and metastasis in vivo. We propose preclinical trials in pancreatic carcinoma (both human and murine orthotopic models) to test SEMA3F purified proteins delivered as daily injections or in slow-release pumps. In addition, we will test SEMA3F retroviral infection to obliterate pancreatic cancer metastasis in the liver. Overall, our plans are to investigate a novel approach and a new target in pancreatic cancer. PUBLIC HEALTH RELEVANCE: Our proposed studies will explore the biology of cancer metastasis and the molecular mechanisms involved in pancreatic adenocarcinoma. Our preclinical trials with Semaphorin 3F may have broader impact on many angiogenic and metastatic cancers.